Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort

Abstract

Aims/hypothesis The aim of this work was to investigate the mechanisms underlying the risk of type 2 diabetes associated with statin treatment in the population-based Metabolic Syndrome in Men (METSIM) cohort. Methods A total of 8,749 non-diabetic participants, aged 45-73 years, were followed up for 5.9 years. New diabetes was diagnosed in 625 men by means of an OGTT, HbA 1c ≥6.5% (48 mmol/mol) or glucose-lowering medication started during the follow-up. Insulin sensitivity and secretion were evaluated with OGTT-derived indices. Results Participants on statin treatment (N=2,142) had a 46% increased risk of type 2 diabetes (adjusted HR 1.46 [95% CI 1.22, 1.74]). The risk was dose dependent for simvastatin and atorvastatin. Statin treatment significantly increased 2 h glucose (2hPG) and glucose AUC of an OGTT at follow-up, with a nominally significant increase in fasting plasma glucose (FPG). Insulin sensitivity was decreased by 24% and insulin secretion by 12% in individuals on statin treatment (at FPG and 2hPG <5.0 mmol/l) compared with individuals without statin treatment ( p<0.01). Decreases in insulin sensitivity and insulin secretion were dose dependent for simvastatin and atorvastatin.Conclusions/interpretation Statin treatment increased the risk of type 2 diabetes by 46%, attributable to decreases in insulin sensitivity and insulin secretion.

Statins and Diabetes: The Plot Thickens

“…The increased risk of diabetes observed in this study is considerably higher than that in the previously mentioned meta-analyses 1 and is similar to that reported in the METSIM study. 4 In addition, the risk is dose-and exposure-dependent, in agreement with previous reports, 2,3 which strengthens the case for a causal role of statins. Similar to the results in previous studies, the authors also report an association with overweight and obesity.…”

“…3 Recent data from the higher-risk population cohort in the Metabolic Syndrome in Men (METSIM) study, however, which included 8749 non-diabetic participants aged 45 to 73 years who were followed for 5.9 years, indicated a 56 % increased risk (11.2 versus 5.8 %) in statin-treated patients, which was dose-dependent for simvastatin and atorvastatin, suggesting that statin treatment may be associated with a much higher risk of diabetes in a population with a high risk of diabetes at baseline. 4 Even in patients with type 2 diabetes, statin treatment is associated with worsening glycemic control. In pooled analyses of nine trials involving 9696 patients over a follow-up period of 3.6 years, mean HbA1c levels increased by 0.2 % in patients randomized to statin versus control treatment.…”

“…5 This dysglycemic effect of statins is apparently due to a reduction in both insulin sensitivity and secretion. 4 In addition, variants in the gene encoding HMG-CoA reductase, the target of statins, are associated with higher body weight, waist circumference, plasma glucose, and insulin concentrations, suggesting that the increased risk of type 2 diabetes due to statins may be partially explained by HMG-CoA reductase inhibition. 6 Furthermore, studies have suggested that statin treatment is related to impaired exercise training and decreased diet compliance.…”

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

“…A total of 248 cardiovascular health‐ and metabolism‐related parameters available in the METSIM cohort (Table S1)17, 28, 29 were analyzed in relation to APOE genotypes. As expected, all determined lipid and lipoprotein parameters differed significantly among the carriers of the different APOE genotypes (Table 1).…”

“…P < 0.05 was considered as statistically significant except in the initial analysis with METSIM cohort, in which the threshold of statistical significance was set as P < 0.0002 ( P < 0.05/248) given 248 cardiovascular health and metabolic parameters compared (Table S1). 17, 28, 29 …”